Protein kinases are key elements in signal transduction pathways responsible for transducing extracellular signals to the nuclei, triggering various biological events. [Schlessinger, J. and Ullrich, A., “Growth factor signaling by receptor tyrosine kinases,” Neuron, 9:383-391 (1992)] The many roles of protein tyrosine kinases (PTKs) in normal cell physiology include cell growth, differentiation, apoptosis, cell mobility and mitogenesis. [Plowman et al., “Receptor tyrosine kinases as targets for drug intervention,” DN&P, 7:334-339 (1994)].
Protein kinases include, for example, but are not limited to, extracellular signal-regulated kinases, p42/ERK2 and p44/ERK1; c-Jun NH2-terminal kinase (JNK); cAMP-responsive element-binding protein kinases (CREB); cAMP-dependent kinase (CAPK); mitogen-activated protein kinase-activated protein kinase (MAPKAP); stress-activated protein kinase p38/SAPK2; mitogen- and stress-activated kinase (MSK); p185neu/Her-2/erbB-2; platelet derived growth factor receptor kinase (PDGFR); colony stimulating factor-1 receptor kinase (CSF1-R); endothelial growth factor receptor kinase (EGF-R); vascular endothelial growth factor kinase (VEGF-R); fibroblast growth factor receptor kinase (FGF-R); protein kinases, PKA, PKC and PKC-α; serine/threonine protein kinase (STK); the Janus family of tyrosine protein kinases, JAK1, JAK2 and JAK 3; human insulin receptor tyrosine kinase; the Src-family of cytoplasmic PTKs, p60c-arc, c-Src, Hck, Fgr and Lyn; Abelson leukemia virus PTK (c-Abl); p56fyn (FYN); p56lck (LCK); cyclin-dependent kinases (CDK1, CDK2, CDK3 and CDK4); NGF receptor kinase (Trk); Alk receptor kinase; IKK-β kinase; Axl/Ufo kinase; Rse/Sky kinase; Syk kinase; ZAP-70 kinase; NIK kinase; Yrk kinase; Fyk kinase; Blk kinase; Csk kinase; Tie-1 and Tie-2 kinase; TrkA, TrkB and Trk C kinases; and human growth factor kinase (HGF).
The disruption of the normal functions of kinases has been implicated in many human diseases, including cancer, diabetes, restenosis, atherosclerosis, fibrosis of the liver and kidney and psoriasis. [Powis, G. and Workman, P., “Signaling targets for the development of cancer drugs,” Anti-Cancer Drug Design, 9:263-277 (1994); Cantley et al., “Oncogenes and signal transduction,” Cell, 64:281-302 (1991); Kolibaba, K. S. and Druker, B. J., “Protein tyrosine kinase and cancer,” Biochim Biophys Acta, 1333:F217-F248 (1997); Merenmies et al., “Receptor tyrosine kinase signaling in vascular development,” Cell Growth Differ, 8:3-10 (1997); Lavelle, F., “American Association for Cancer Research 1997: Progress and New Hope in the Fight Against Cancer,” Exp Opin Invest Drugs, 6:771-775 (1997); and Shawver et al., “Receptor tyrosine kinases as targets for inhibition of angiogenesis,” Drug Discovery Today, 2:50-63 (1997)] In fact, about 30% of human breast and ovarian cancer patients have exhibited increased expression of Her-2 (p185neu). [Plowman et al., “Receptor tyrosine kinases as targets for drug intervention,” DN&P, 7:334-339 (1994)] Platelet-derived growth factor receptor tyrosine kinases have been associated with human malignancies, arterial restenosis, and fibrosis of the liver, lung and kidney. Colony stimulating factor-1 receptor has been implicated in bone remodeling and hematopoiesis. Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR. [Waltenberger et al. (Ludwig Institute for Cancer Research, Uppsala Branch, Sweden), “Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor,” J. Biol. Chem., 269:26988-95 (1994)]. VEGF receptor tyrosine kinases have been implicated in tumor angiogenesis, psoriasis, rheumatoid arthritis, atherosclerosis, and ocular diseases. [Shawver et al., “Receptor tyrosine kinases as targets for inhibition of angiogenesis,” Drug Discovery Today, 2:50-63 (1997)]
Further examples of the role of inappropriate kinase activities in various disease states and conditions include, but are not limited to, JAK2 kinase: myelo- and lymphoproliferative disorders [Science, 278:1309-1312 (1997); Blood, 93:2369-2379 (1999)]; Fyn kinase: T-cell leukemia and lymphoma [Curr. Opin. Immunol., 6:372-379 (1994)]; Fgr, Lyn and Hck kinases: rheumatoid arthritis and Crone's disease [J. Exper. Med., 185:1661-1670 (1997)]; Lck kinase: T-cell leukemia and lymphoma [Curr. Opin. Immunol., 6:372-379 (1994)]; Csk kinase: rheumatoid arthritis [J. Clin. Invest., 104:137-146 (1999)]; PKA and PKC kinases: diabetic complications such as blindness [Proc. N.Y. Acad. Sci., 89:11059 (1992)]; c-Abl kinase: chronic myelogenous leukemia [Blood, 93:3973-3982 (1999); J. Cancer Res. Clin. Oncol, 124:643-660 (1998)]; FGFR kinase: Crouzon syndrome, achondroplasia, thanatophoric dysplasia, leukemia, lymphoma and other autoimmune disorders [Nature Genetics, 8:98 (1994); Cell, 78:335 (1994); Nature Genetics, 13:233 (1996)]; ERK1 and ERK2 kinases: head and neck carcinoma [Br. J. Cancer, 80:1412-1419 (1999)]; Tie-1 and Tie-2 kinases: breast cancer [Cancer Research, 59:3185-3191 (1999); Br. J. Cancer, 77:51-56 (1998)]; TrkA, TrkB and TrkC kinases: neuroblastoma [Clin. Cancer Res., 5:1491-1496 (1999)]; IKK-β kinase: inflammation and rheumatoid arthritis [Cell, 90:373-383 (1997); Nature, 388:548-554 (1997); Published PCT application WO 99/34000]; MAPKAP kinase: inflammation and rheumatoid arthritis [Nat. Cell Biol., 1:94-97 (1999)]; p38/SAPK2 kinase: inflammation and rheumatoid arthritis [J. Bio. Chem., 274:19559-19564 (1999); Nature, 372:739-746 (1994); Ann. N.Y. Acad. Sci., 696:149-170 (1993)]; VEGFR kinase: melanoma, cancer, tumor angiogenesis, psoriasis, rheumatoid arthritis, atherosclerosis, ocular diseases and vascular disorders [Blood, 94:984-993 (1999); McMahon et al., “Protein kinase inhibitors: structural determinants for target specificity,” Drug Discovery & Development, 1:131-146 (1998)]; HGF kinase: carcinoma and cancer [Int. J. Cancer, 82:449-458 (1999); Jikken Igaku, 16:2016-2025 (1998)]; p185neu/Her-2 kinase: breast cancer [Nature, 385:540-544 (1997)]; NIK kinase: inflammation [Nature (London), 398:252-256 (1999)]; Axl/Ufo kinase: myeloid leukemia and prostate cancer [Nature, 368:753-756 (1993); Cancer Detect. Prev., 23:325-332 (1999)]; Rse/Sky kinase: tumors and cell proliferation and breast cancer [J. Biol. Chem., 270:6872-6880 (1995)]; c-Src kinase: colon and breast cancer [Biochem. Biophys. Res. Commun., 250:27-31 (1998); Bone (Osaka), 10:135-144 (1996)]; NGF receptor kinase-Trk: colon cancer [Proc. Nat. Acad. Sci., 91:83-87 (1994); Proc. Nat. Acad. Sci., 84:2251-2253 (1987)]; PDGF kinase: chronic myelomonocytic leukemia, arteriosclerosis and fibrosis of the liver, lung and kidney [Oncogene, 7:237-242 (1992); New Engl. J. Med., 314:488-500 (1986)]; Alk receptor kinase: lymphoma [Cell, 77:307-316 (1994); Blood, 93:3088-3095 (1999); Oncogene, 14:4035-4039 (1997)]; Syk kinase: anaplastic large cell lymphoma [Science, 263:1281-1284 (1994); FEBS Lett., 427:139-143 (1998); J. Biol. Chem., 273:4035-4039 (1998)]; HIRTK kinase: diabetes [Science, 284:974-977 (1999); Diabetes, 38:1508 (1989)]; ZAP-70 kinase: immune disorders [Curr. Biol., 9:203-206 (1999); EGFR kinase: carcinoma, psoriasis [Cancer Research, 57:4838-4848 (1997); Cell, 61:203-212 (1990); J. Oncology, 4:277-296 (1994); U.S. Pat. No. 5,654,307 (Aug. 5, 1997)]; JAK3 kinase: immune suppression, leukemia and organ transplant rejection [Adv. Immunology, 60:1-35 (1995); Leuk. Lymphoma, 32:289-297 (1999)]; Science, 270:797-800 (1995)]; and CDK2 kinase: bladder cancer (Published PCT application WO97/16452).
Inappropriate protein kinase activities thus represent attractive targets for therapeutic intervention and in fact, several small molecule kinase inhibitor compounds have been disclosed. Natural products such as staurosporine, lavendustin A, erbstatin, genistein and flavopiridol for example, have been shown to be effective kinase inhibitors. In addition, a number of synthetic tyrosine kinase inhibitors have also been introduced. [McMahon et al., “Protein kinase inhibitors: structural determinants for target specificity,” Drug Discovery & Development, 1:131-146 (1998)]. The present invention relates to novel compounds effective as inhibitors of inappropriate kinase activities.